Antihypertensives

Question 1

Examples of ACE Inhibitors

Answer 1

Captopril, Enalapril, Lisinopril, Moexipril, Perindopril, Quinapril, Ramipril and Trandolapril.

Question 2

Cautions of ACE Inhibitors

Answer 2

Not for use in people with renal problems due to changes in glomerular filtration.
Not for use in pregnant women due to possible effects on foetus and amniotic fluid production.
Not for use in breast-feeding women due to risks of decreased milk production or passing into milk.

Question 3

Action of ACE Inhibitors

Answer 3

Block the ACE enzyme therefore preventing the conversion of Angiotensin 1 to Angiotensin 2. This stops vasoconstriction and therefore lowers TPR and as a result lowers BP.

Question 4

How is BP controlled by: Baroreceptors?

Answer 4

Baroreceptors in the aorta and the carotid arteries which deliver blood to the brain respond to stretch. If stimulated or not being affected, information is sent to the brain and specifically the medulla oblongata in the cardiovascular (vasomotor) centre.
If BP is high: medulla stimulates vasodilation and decreases cardiac rate and output.
If BP is low: medulla stimulates vasoconstriction and increases cardiac rate and output.
Medulla mediates effects through ANS.

Question 5

How is BP controlled by: Renin-Angiotensin-Aldosterone system?

Answer 5

Low BP in kidney or poor oxygenation of nephrons causes juxtaglomerular cells (cells that monitor BP and blood flow into the glomerulus) to release renin. Renin moves to liver via bloodstream and converts angiontensinogen (produced in liver) to angiontensin 1 (A1). A1 moves in bloodstream to lungs where metabolic cells in the alveoli and bronchial mucosa use angiotensin converting enzyme (ACE) to convert A1 to angiotensin 2 (A2). A2 reacts with A2 receptor sites on blood vessels to cause intense vasoconstriction, thereby raising TPR, raising BP, restoring blood flow to kidneys causing decrease of renin release.

A2 also stimulates adrenal cortex to release aldosterone, which acts on nephrons to cause retention of sodium (Na) and water. This increases blood volume and therefore BP. Osmoreceptors in hypothalamus are stimulated by blood rich in Na and ADH is released causing further retention of water causing increase in blood volume and BP, increasing blood flow to kidney and decreasing release of renin

Question 6

Side effects of ACE inhibitors.

Answer 6

ACE inhibitors stimulate release of bradykinin which is involved with inflammation causing a rash. Also vasodilates and irritates airways causing irritation and cough.
GI distress, skin effects, cardiac arrhythmias, mood and sleep disturbances, reflex tachycardia, ulcers, constipation, liver injury, renal insufficiency, renal failure, alopecia, dermatitis and photosensitivity. Fatal effects include MI, pancytopenia (depression of all cellular elements in blood) and serious to fatal airway obstructions.
Also results in slightly raised potassium in serum and loss of serum sodium and fluid.
Hypotension!

Question 7

How is BP controlled generally?

Answer 7

BP is determined by heart rate, stroke volume (amount of blood pumped out with each beat) and TPR (resistance of muscular arteries to blood being pumped through).
Small arterioles most important in regard to TPR as they can almost stop blood flow to capillary beds due to their narrow lumen. Stopping blood flow causes pressure to build up behind the block. Arterioles are responsive to stimulation from the SNS - they constrict when SNS is stimulated via alpha-1 adrenoreceptors, which causes TPR and BP to increase. Body uses this responsiveness to regulate BP on a minute to minute basis to ensure sufficient blood flow to the brain.

Question 8

What are the stages for treating hypertension?

Answer 8

Step 1: Lifestyle changes - weight reduction, smoking cessation, alcohol intake reduction, salt intake reduction (all of these factors shown to increase BP). Increasing physical exercise - decreases BP and improves cardiovascular tone and reserve.

Step 2: Under 55 uses ACE inhibitors.

Step 3: Over 55 or African or Carribean descent of any age - Calcium Channel Blocker (CCB) or thiazide diuretic.

Step 4: If initial was CCB or thiazide and a further drug required - ACE inhibitor.
If ACE inhibitor was initial - CCB or thiazide.

Step 5: If three drugs are required then ACE, CCB and thiazide.

ARB’s can be used in place of ACE if not tolerated.

B-blockers not used as first line because of risks of developing type 2 diabetes and not performing as well as antihypertensives.

Question 9

Pharmacokinetics of ACE inhibitors

Answer 9

Well absorbed, widely distributed, metabolized in liver and excreted in faeces and urine. Can cross the placenta and are associated with foetal abnormalities. Detected in breast milk.

Question 10

Key ACE inhibitor: Ramipril facts

Answer 10

Ramipril
Indications: Severe hypertension, resistant to other therapy, CHF, diabetic neuropathy, left ventricular function after an MI.

Action: Blocks ACE from converting A1 to A2, causing decrease in BP, decrease in aldosterone production, small increase in serum potassium levels along with sodium and fluid loss.

Pharmacokinetics:
Route: Oral
Onset: 15 minutes
Peak: 30-90 minutes

Half life: 2 hours, excreted in urine

Adverse effects: Cough, tachycardia, MI, rash, pruritus, gastric irritation, aphthous ulcers, peptic ulcers, proteinuria and bone marrow suppression.

Question 11

Four types of anti-hypertensives are:

Answer 11

ACE Inhibitors
Beta-Blockers
Calcium Channel Blockers
Diuretics

Question 12

ACE inhibitors are drug of choice for patients with congestive cardiac failure because…

Answer 12

They reduce cardiac workload.

Question 13

Why do bradykinins not usually have any affect?

Answer 13

A2 converts bradykinins into an inactive form. ACE inhibitors prevent the formation of A2 and therefore bradykinins are active.
NSAIDs can be used to relieve problems caused by bradykinins.

Question 14

Examples of Angiotensin Receptor Antagonists (ARB).

Answer 14

Losartan, Candesartan, Valsartan, Eprosartan, Irbesartan, Olmesartan, Telmisartan.

Question 15

Mechanism of action for ARBs.

Answer 15

Selectively block A2 receptor sites to stop vasoconstriction and the release of aldosterone from the adrenal cortex.

Question 16

Why does suppression of aldosterone cause increase in potassium and loss of serum sodium and fluid?

Answer 16

Aldosterone causes the retention of Na and water at the expense of K. Therefore if aldosterone secretion is suppressed, the reverse will occur.

Question 17

Why are ARB’s used in place of ACE inhibitors sometimes.

Answer 17

Have mostly the same effect due to the fact that one blocks the formation of A2 and the other blocks receptor sites, therefore any reaction caused by A2. The only notable action that isnt affected is that because A2 is formed, it does convert bradykinin into it’s inactive form preventing accumulation of kinins.

Question 18

Pharmacokinetics of ARB’s

Answer 18

Similar to ACE inhibitors. Metabolized in liver by cytochrome P450. Can result in stillbirth if given in second or third trimester of pregnancy.

Question 19

Side effects of ARB’s.

Answer 19

Headaches, dizziness, syncope, weakness, hypotension, GI complaints - diarrhoea, abdominal pain, nausea, dry mouth, tooth pain; URT infections, rash, dry skin, alopecia, hyperkalaemia and angioedema.

Question 20

Drug interactions of ACE inhibitors.

Answer 20

Risk of hypersensitivity reactions increase if taken win allopurinol.

Question 21

Drug interactions of ARB’s.

Answer 21

Increased risk of decreased serum levels and loss of effectiveness if taken with phenobarbital.

Question 22

Contraindications of ARB’s.

Answer 22

Similar to ACE inhibitors. Not to be taken if allergic to.

Question 23

Examples of Calcium Channel Blockers (CCB).

Answer 23

Amlodipine, Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine, Nisoldipine, Verapamil.

Question 24

Mechanism of action for CCBs.

Answer 24

Calcium is needed to help muscles to contract. CCB’s prevent Ca from being able to move across the membranes of myocardial and arterial muscle cells into cardiac and smooth muscle cells when they are stimulated. This lowers the action potential needed and blocks muscle cell contraction, depressed myocardial contractility, slows cardiac impulse formation in conductive tissues and also causes a loss of smooth muscle tone, vasodilation and a decrease in TPR, thus reducing cardiac workload and decreasing BP, decreasing venous return and decreasing myocardial oxygen consumption.

Question 25

Key ARB: Losartan Facts

Answer 25

Losartan

Treats: Alone or part of combination for hypertension, diabetic neuropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and hypertension.

Actions: Selectively blocks binding of A2 to specific tissue receptors found in smooth muscle and adrenal glands. Blocks vasoconstriction and release of aldosterone associated with A-R-A system.

Pharmacokinetics: 
Route: Oral
Onset: Varies
Peak 1-3 hours
Duration: 24 hours

Half life: 2 hours, then for the metabolites 6-9 hours, metabolised in liver and excreted in urine and faeces.

Side effects: Dizziness, headaches, abdominal pain, symptoms of URT infection, cough, back pain, fever, muscle weakness and hypotension.

Question 26

Pharmacokinetics of CCBs.

Answer 26

Well absorbed, metabolized by liver and excreted in urine and faeces. No studies on effects on foetus, dangerous in animals on foetus so not used in pregnancy unless benefit to woman outweighs risk to foetus.

Question 27

Cautions of CCBs.

Answer 27

Not for patients with heart block or sick sinus syndrome - could be exacerbated by conduction slowing effects, hepatic or renal dysfunction - could alter metabolism and excretion, pregnancy or breastfeeding - risks of effects on foetus or child.

Question 28

Side effects of CCBs

Answer 28

Related to effects on cardiac output and smooth muscle. CNS effects - dizziness, lightheadedness, headache, fatigue; GI problems; nausea and hepatic injury related to direct toxic effects on hepatic cells. Cardiovascular effects: hypotension, bradycardia, peripheral oedema and heart block. Skin flushing and rash.

Question 29

Drug interactions for CCBs.

Answer 29

Vary between each drug. Most serious is increase in serum levels and toxicity of cyclosporine if taken with diltiazem.